Donor T-cells mediating graft-versus-leukemia (GVL) effects can cure patients with a variety of different hematological malignancies. Until recently, few studies supported a similar susceptibility of solid tumors to allogeneic immunotherapy. It has recently been reported that metastatic RCC can regress following nonmyeloablative allogeneic HCT as a consequence of a donor immune mediated graft-versus-tumor (GVT) effect. Childs et al., Blood 94:3234-41, 1999. Although these GVT effects can be durable and sometimes complete, more than half of patients undergoing HCT fail to achieve a disease response. Bregni et al., Bone Marrow Transplant 38:527-37, 2006. A better understanding of the immune cells and their target antigens that mediate the regression of these tumors is needed to develop more effective transplant approaches for RCC.
For hematological malignancies, GVL effects appear to be primarily mediated by allogeneic T-cells targeting polymorphic peptides expressed on malignant T-cells of the recipient (i.e., minor histocompatibility antigens, mHas). Several lines of clinical evidence suggest donor T-cells targeting antigens expressed on the tumor also mediate regression of metastatic renal cancer. The majority of patients who achieve a disease response have tumor growth early after transplantation, when the newly engrafted donor immune system is suppressed by cyclosporine or when mixed T-cell chimerism leading to T-cell “tolerance” of host tissues (including the tumor) occurs. In responding patients, tumor regression is typically delayed by 4-6 months occurring after immunosuppression has been withdrawn following the conversion from mixed to full donor T-cell chimerism. As observed with hematological malignancies, graft-versus-host disease (GVHD) is also associated with disease regression. These clinical observations and recent in vitro findings suggest regression of metastatic RCC may result from alloreactive T-cells targeting mHas broadly expressed on both normal tissues and tumor cells of the recipient. Seifarth et al., J Virol 79:341-52, 2005. However, the observation that tumor shrinkage sometimes occurs in the absence or temporally distant from GVHD implies antigens over-expressed or even selectively expressed on the tumor might also be a target for immune cells mediating RCC regression. Although cytotoxic T-lymphocytes (CTLs) have been used to identify antigens expressed on a variety of tumors, to date relatively few RCC-associated antigens recognized by human CTL have been identified. Bock, M. and Stoye, J. P., Curr Opin Genet Dev 10:651-5, 2000; Childs et al., N Engl J Med 343:750-8, 2000; Li et al., Nature 409:847-9, 2001; Lower et al., Proc Natl Acad Sci USA 93:5177-84, 1996; Smit, A. F., Curr Opin Genet Dev 9:657-63, 1999; Tykodi et al., Clin Cancer Res 10:7799-811, 2004.
A need exists in the art for a better understanding of the immune cells and their target antigens that mediate the regression of solid tumors to develop more effective transplant approaches for RCC. The current treatment of renal cell carcinoma cancers can have adverse effects on subjects undergoing such therapies and are usually ineffective. Accordingly, there is a need for improved, safer treatments that have long-lasting protective effects for the prevention and treatment of neoplastic disease, for example, renal cell carcinoma. In particular, there is a need for treatments that are more specific and less toxic than the currently available therapeutic agents.